Treatment of Psychiatric Conditions

ABSTRACT

The number of acne lesions in a human subject is reduced by administering to the subject a pharmaceutical composition that includes a pharmaceutically acceptable carrier and a therapeutically effective amount of an agent that selectively binds IL-1α. Anxiety and other psychiatric conditions are also improved with this treatment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 13/437,159 filed on Apr. 2, 2012, which claimspriority from U.S. provisional patent application No. 61/470,538 filedon Apr. 1, 2011.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

Not applicable.

FIELD OF THE INVENTION

The invention relates generally to the fields of medicine, dermatology,and immunology. More particularly, the invention relates to the use ofantibodies (Abs) which specifically bind interleukin-1α (IL-1α) to treatinflammatory skin diseases as well as psychiatric conditions.

BACKGROUND

Inflammatory skin disorders acne, rosacea, and psoriasis afflict manymillions of people. While not usually lethal, these conditions can causephysical discomfort and affect emotional well-being. There are currentlya large number of different treatments for inflammatory skin disordersincluding corticosteroids, vitamin D analogs, coal tar, ultravioletlight, retinoids, methotrexate, cyclosporine, hydroxyurea, antibiotics,and biologic agents such as TNFalpha inhibitors. While these therapieshave proven useful for many patients, many cause undesirableside-effects and none are ideal for every situation.

SUMMARY

The invention is based on the discovery that a mAb that specificallybinds IL-1α is useful for treating acne vulgaris and various psychiatricconditions (such as anxiety and poor self-image).

Accordingly, the invention features a method of reducing the number ofacne lesions in a human subject, as well as a method of treating apsychiatric condition (e.g., anxiety, depression, or poor self-image) ina human subject. These methods can include the step of administering tothe subject a pharmaceutical composition including a pharmaceuticallyacceptable carrier and an amount of an agent that selectively bindsIL-1α effective to reduce to reduce the number of acne lesions orimprove a psychiatric condition in the subject. The agent can be ananti-IL-1α antibody such as a monoclonal antibody (e.g., of the IgG1isotype), a monoclonal antibody that includes a complementaritydetermining region of MABp1, or MABp1.

Another aspect of the invention features a method of reducing skininflammation in a human subject by administering to the subject apharmaceutical composition including a pharmaceutically acceptablecarrier and an amount of an anti-IL-1α Ab (or other agent thatspecifically and/or selectively binds IL-1a) effective to reduce asymptom of skin inflammation (e.g., redness, swelling, leukocyteinfiltration, lesion development, or lesion number) in the subject by atleast about 10% (e.g., at least 8, 9, 10, 15, 17, 20, 30, 40, 50, 60,70, 80, 90, or 100%) as measured by any standard dermatological test.The anti-IL-1α Ab can be a mAb such as an IgG1. The anti-IL-1α Ab can bethe mAb designated as MABp1 or a mAb that includes one or morecomplementarity determining regions (CDRs) of MABp1. The pharmaceuticalcomposition can be administered to the subject by injection,subcutaneously, intravenously, intramuscularly, or intradermally. In themethod, the dose can be at least 0.25 (e.g., at least 0.2, 0.5, 0.75, 1,2, 3, 4, or 5) mg/ml.

In other aspects, the invention includes use of an agent thatselectively binds IL-la to treat acne and/or a psychiatric condition inthe subject, and a pharmaceutical composition for treating acne and/or apsychiatric condition in the subject, the composition comprising anagent that selectively binds IL-1α. In the foregoing, the agent can bean anti-IL-1α antibody such as a monoclonal antibody (e.g., of the IgG1isotype), or a monoclonal antibody that includes a CDR of MABp1, orMABp1.

Unless otherwise defined, all technical terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs. Commonly understood definitions ofbiological terms can be found in Rieger et al., Glossary of Genetics:Classical and Molecular, 5th edition, Springer-Verlag: New York, 1991;and Lewin, Genes V, Oxford University Press: New York, 1994. Commonlyunderstood definitions of medical terms can be found in Stedman'sMedical Dictionary, 27^(th) Edition, Lippincott, Williams & Wilkins,2000.

As used herein, an “antibody” or “Ab” is an immunoglobulin (Ig), asolution of identical or heterogeneous Igs, or a mixture of Igs. An “Ab”can also refer to fragments and engineered versions of Igs such as Fab,Fab′, and F(ab′)₂ fragments; and scFv's, heteroconjugate Abs, andsimilar artificial molecules that employ Ig-derived CDRs to impartantigen specificity. A “monoclonal antibody” or “mAb” is an Ab expressedby one clonal B cell line or a population of Ab molecules that containsonly one species of an antigen binding site capable of immunoreactingwith a particular epitope of a particular antigen. A “polyclonal Ab” isa mixture of heterogeneous Abs. Typically, a polyclonal Ab will includemyriad different Ab molecules which bind a particular antigen with atleast some of the different Abs immunoreacting with a different epitopeof the antigen. As used herein, a polyclonal Ab can be a mixture of twoor more mAbs.

An “antigen-binding portion” of an Ab is contained within the variableregion of the Fab portion of an Ab and is the portion of the Ab thatconfers antigen specificity to the Ab (i.e., typically thethree-dimensional pocket formed by the CDRs of the heavy and lightchains of the Ab). A “Fab portion” or “Fab region” is the proteolyticfragment of a papain-digested Ig that contains the antigen-bindingportion of that Ig. A “non-Fab portion” is that portion of an Ab notwithin the Fab portion, e.g., an “Fc portion” or “Fc region.” A“constant region” of an Ab is that portion of the Ab outside of thevariable region. Generally encompassed within the constant region is the“effector portion” of an Ab, which is the portion of an Ab that isresponsible for binding other immune system components that facilitatethe immune response. Thus, for example, the site on an Ab that bindscomplement components or Fc receptors (not via its antigen-bindingportion) is an effector portion of that Ab.

When referring to a protein molecule such as an Ab, “purified” meansseparated from components that naturally accompany such molecules.Typically, an Ab or protein is purified when it is at least about 10%(e.g., 9%, 10%, 20%, 30% 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%,99.9%, and 100%), by weight, free from the non-Ab proteins or othernaturally-occurring organic molecules with which it is naturallyassociated. Purity can be measured by any appropriate method, e.g.,column chromatography, polyacrylamide gel electrophoresis, or HPLCanalysis. A chemically-synthesized protein or other recombinant proteinproduced in a cell type other than the cell type in which it naturallyoccurs is “purified.”

By “bind”, “binds”, or “reacts with” is meant that one moleculerecognizes and adheres to a particular second molecule in a sample, butdoes not substantially recognize or adhere to other molecules in thesample. Generally, an Ab that “specifically binds” another molecule hasa K_(d) greater than about 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, or 10¹²liters/mole for that other molecule. An Ab that “selectively binds” afirst molecule specifically binds the first molecule at a first epitopebut does not specifically bind other molecules that do not have thefirst epitope. For example, an Ab which selectively binds IL-1alphaspecifically binds an epitope on IL-1alpha but does not specificallybind IL-1beta (which does not have the epitope).

A “therapeutically effective amount” is an amount which is capable ofproducing a medically desirable effect in a treated animal or human(e.g., amelioration or prevention of a disease or symptom of a disease).

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,suitable methods and materials are described below. All applications andpublications mentioned herein are incorporated by reference in theirentirety. In the case of conflict, the present specification, includingdefinitions will control. In addition, the particular embodimentsdiscussed below are illustrative only and not intended to be limiting.

DETAILED DESCRIPTION

The invention encompasses compositions and methods for reducing skininflammation including ameliorating one or more symptoms of adermatological pathology in a subject. The below described preferredembodiments illustrate adaptation of these compositions and methods.Nonetheless, from the description of these embodiments, other aspects ofthe invention can be made and/or practiced based on the descriptionprovided below.

General Methodology

Methods involving conventional immunological and molecular biologicaltechniques are described herein. Immunological methods (for example,assays for detection and localization of antigen-Ab complexes,immunoprecipitation, immunoblotting, and the like) are generally knownin the art and described in methodology treatises such as CurrentProtocols in Immunology, Coligan et al., ed., John Wiley & Sons, NewYork. Techniques of molecular biology are described in detail intreatises such as Molecular Cloning: A Laboratory Manual, 2nd ed., vol.1-3, Sambrook et al., ed., Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., 2001; and Current Protocols in Molecular Biology,Ausubel et al., ed., Greene Publishing and Wiley-Interscience, New York.Ab methods are described in Handbook of Therapeutic Abs, Dubel, S., ed.,Wiley-VCH, 2007. General methods of medical treatment are described inMcPhee and Papadakis, Current Medical Diagnosis and Treatment 2010,49^(th) Edition, McGraw-Hill Medical, 2010; and Fauci et al., Harrison'sPrinciples of Internal Medicine, 17^(th) Edition, McGraw-HillProfessional, 2008. Methods in dermatology are described in James etal., Andrews' Diseases of the Skin: Clinical Dermatology—Expert Consult,11^(th) Ed., Saunders, 2011; and Burns et al., Rook's Textbook ofDermatology, 8^(th) Ed., Wiley-Blackwell, 2010.

Treatment

The compositions and methods described herein are useful for treatingskin inflammation (e.g., associated with rosacea, eczema, psoriasis,xerosis, dermatitis, acne, pyoderma gangrenosum, urticaria, lichenoiddisorders, bullous diseases such as bullous pemphigoid, cutaneousvasculitis, and granulomatous skin diseases) as well as psychiatricconditions (e.g., anxiety, depression, and poor self image) in amammalian subject by administering to the subject a pharmaceuticalcomposition including an amount of an anti-IL-1α Ab effective to improveat least one characteristic of the inflammation (e.g., reduction in thenumber or size of lesions, reduction of redness, and reduction initchiness) or psychiatric condition in the subject. The mammaliansubject might be any that suffers from skin inflammation or apsychiatric condition including, human beings, dogs, cats, horses,cattle, sheep, goats, and pigs. Human subjects might be male, female,adults, children, seniors (65 and older), and those with other diseases.Particularly preferred subjects are those whose disease has progressedor failed to respond after treatment with other anti-inflammatory oranti-microbial agents such as retinoids, antibiotics, steroids orcytokine inhibitors such as TNFalpha inhibitors. Subjects who havedeveloped a human anti-human antibody response due to prioradministration of therapeutic antibodies are preferred when theanti-IL-1α Ab is a true human Ab (e.g., one that is naturally expressedin a human subject) such as MABp1. Any type of inflammatory skin diseasesusceptible to treatment with an anti-IL-1α Ab might be targeted.Anti-1α Ab administration is thought to be particularly effective fortreating acne vulgaris and psoriasis vulgaris.

Antibodies and other Agents that Target IL-1α

Any suitable type of Ab that specifically binds IL-1α and reduces acharacteristic of a psychiatric condition, skin inflammation and/or aninflammatory skin disease such as acne vulgaris or psoriasis vulgaris ina subject might be used in the invention. For example, the anti-IL-1α Abused might be mAb, a polyclonal Ab, a mixture of mAbs, or an Ab fragmentor engineered Ab-like molecule such as an scFv. The Ka of the Ab ispreferably at least 1×10⁹ M⁻¹ or greater (e.g., greater than 9×10¹⁰ M⁻¹,8×10¹⁰ M⁻¹, 7×10¹⁰ M⁻¹, 6×10¹⁰ M⁻¹, 5×10¹⁰ M⁻¹, 4×10¹⁰ M⁻¹, 3×10¹⁰ M⁻¹,2×10¹⁰ M⁻¹, or 1×10¹⁰ M⁻¹). In a preferred embodiment, the inventionutilizes a fully human mAb that includes (i) an antigen-binding variableregion that exhibits very high binding affinity (e.g., at least nano orpicomolar) for human IL-1α and (ii) a constant region. The human Ab ispreferably an IgG1, although it might be of a different isotype such asIgM, IgA, or IgE, or subclass such as IgG2, IgG3, or IgG4. One exampleof a particularly useful mAb is MABp1, an IL-1α-specific IgG1 mAbdescribed in U.S. patent application Ser. No. 12/455,458 filed on Jun.1, 2009. Other useful mAbs are those that include at least one butpreferably all the CDRs of MABp1.

Because B lymphocytes which express Ig specific for human IL-1α occurnaturally in human beings, a presently preferred method for raising mAbsis to first isolate such a B lymphocyte from a subject and thenimmortalize it so that it can be continuously replicated in culture.Subjects lacking large numbers of naturally occurring B lymphocyteswhich express Ig specific for human IL-1α may be immunized with one ormore human IL-1α antigens to increase the number of such B lymphocytes.Human mAbs are prepared by immortalizing a human Ab secreting cell(e.g., a human plasma cell). See, e.g., U.S. Pat. No. 4,634,664.

In an exemplary method, one or more (e.g., 5, 10, 25, 50, 100, 1000, ormore) human subjects are screened for the presence of such humanIL-1α-specific Ab in their blood. Those subjects that express thedesired Ab can then be used as B lymphocyte donors. In one possiblemethod, peripheral blood is obtained from a human donor that possesses Blymphocytes that express human IL-1α-specific Ab. Such B lymphocytes arethen isolated from the blood sample, e.g., by cells sorting (e.g.,fluorescence activated cell sorting, “FACS”; or magnetic bead cellsorting) to select B lymphocytes expressing human IL-1α-specific Ig.These cells can then be immortalized by viral transformation (e.g.,using EBV) or by fusion to another immortalized cell such as a humanmyeloma according to known techniques. The B lymphocytes within thispopulation that express Ig specific for human IL-1α can then be isolatedby limiting dilution methods (e.g., cells in wells of a microtiter platethat are positive for Ig specific for human IL-1α are selected andsubcultured, and the process repeated until a desired clonal line can beisolated). See, e.g., Goding, MAbs: Principles and Practice, pp. 59-103,Academic Press, 1986. Those clonal cell lines that express Ig having atleast nanomolar or picomolar binding affinities for human IL-1α arepreferred. MAbs secreted by these clonal cell lines can be purified fromthe culture medium or a bodily fluid (e.g., ascites) by conventional Igpurification procedures such as salt cuts, size exclusion, ion exchangeseparation, and affinity chromatography.

Although immortalized B lymphocytes might be used in in vitro culturesto directly produce mAbs, in certain cases it might be desirable to useheterologous expression systems to produce mAbs. See, e.g., the methodsdescribed in U.S. patent application Ser. No. 11/754,899. For example,the genes encoding an mAb specific for human IL-1α might be cloned andintroduced into an expression vector (e.g., a plasmid-based expressionvector) for expression in a heterologous host cell (e.g., CHO cells, COScells, myeloma cells, and E. coli cells). Because Igs include heavy (H)and light (L) chains in an H₂L₂ configuration, the genes encoding eachmay be separately isolated and expressed in different vectors.

Although generally less preferred due to the greater likelihood that asubject will develop an anti-Ab response, chimeric mAbs (e.g.,“humanized” mAbs), which are antigen-binding molecules having differentportions derived from different animal species (e.g., variable region ofa mouse Ig fused to the constant region of a human Ig), might be used inthe invention. Such chimeric Abs can be prepared by methods known in theart. See, e.g., Morrison et al., Proc. Nat'l. Acad. Sci. USA, 81:6851,1984; Neuberger et al., Nature, 312:604, 1984; Takeda et al., Nature,314:452, 1984. Similarly, Abs can be humanized by methods known in theart. For example, mAbs with a desired binding specificity can behumanized by various vendors or as described in U.S. Pat. No. 5,693,762;U.S. Pat. No. 5,530,101; or U.S. Pat. No. 5,585,089.

The mAbs described herein might be affinity matured to enhance orotherwise alter their binding specificity by known methods such as VHand VL domain shuffling (Marks et al. Bio/Technology 10:779-783, 1992),random mutagenesis of the hypervariable regions (HVRs) and/or frameworkresidues (Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813, 1994;Schier et al. Gene 169:147-155, 1995; Yelton et al. J. Immunol.155:1994-2004, 1995; Jackson et al., J. Immunol. 154(7):3310-9, 1995;and Hawkins et al, J. Mol. Biol. 226:889-896, 1992. Amino acid sequencevariants of an Ab may be prepared by introducing appropriate changesinto the nucleotide sequence encoding the Ab. In addition, modificationsto nucleic acid sequences encoding mAbs might be altered (e.g., withoutchanging the amino acid sequence of the mAb) for enhancing production ofthe mAb in certain expression systems (e.g., intron elimination and/orcodon optimization for a given expression system). The mAbs describedherein can also be modified by conjugation to another protein (e.g.,another mAb) or non-protein molecule. For example, a mAb might beconjugated to a water soluble polymer such as polyethylene glycol or acarbon nanotube (See, e.g., Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605, 2005). See, U.S. patent application Ser. No. 11/754,899.

Preferably, to ensure that high titers of human IL-1α-specific mAb canbe administered to a subject with minimal adverse effects, the mAbcompositions of the invention are at least 0.5, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90,95, 96, 97, 98, 99, 99.9 or more percent by weight pure (excluding anyexcipients). The mAb compositions of the invention might include only asingle type of mAb (i.e., one produced from a single clonal B lymphocyteline) or might include a mixture of two or more (e.g., 2, 3, 4, 5, 6, 7,8, 9, 10 or more) different types of mAbs.

To modify or enhance their function, the human IL-1α mAbs might beconjugated with another molecule such as a cytotoxin. A human IL-1αspecific mAb might be conjugated with one or more cytotoxins to moreeffectively kill cells expressing IL-1α. Cytotoxins for use in theinvention can be any cytotoxic agent (e.g., molecule that can kill acell after contacting the cell) that can be conjugated to a human IL-1αspecific mAb. Examples of cytotoxins include, without limitation,radionuclides (e.g., 35S, ¹⁴C, ³²P, ¹²⁵I, ¹³¹I, ⁹⁰Y, ⁸⁹Zr, ²⁰¹Tl, ¹⁸⁶Re,¹⁸⁸Re, ⁵⁷Cu, ²¹³Bi, and ²¹¹At), conjugated radionuclides, andchemotherapeutic agents. Further examples of cytotoxins include, but arenot limited to, antimetabolites (e.g., 5-fluorouricil (5-FU),methotrexate (MTX), fludarabine, etc.), anti-microtubule agents (e.g.,vincristine, vinblastine, colchicine, taxanes (such as paclitaxel anddocetaxel), etc.), alkylating agents (e.g., cyclophasphamide, melphalan,bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g., cisplatin(also termed cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.),anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibioticagents (e.g., mitomycin-C), topoisomerase inhibitors (e.g., etoposide,tenoposide, and camptothecins), or other cytotoxic agents such as ricin,diptheria toxin (DT), Pseudomonas exotoxin (PE) A, PE40, abrin, saporin,pokeweed viral protein, ethidium bromide, glucocorticoid, anthrax toxinand others. See, e.g., U.S. Pat. No. 5,932,188.

While the IL-1α specific Abs described above are preferred for use inthe invention, in some cases, other agents that specifically targetIL-1α might be used so long as their administration leads to improvementof a characteristic of an inflammatory skin disease and/or a psychiatriccondition. These other agents might include vaccines that cause theproduction of anti- IL-1α Abs, proteins or peptides that bind IL-1α, andsmall organic molecules which specifically target IL-1α. Those that donot specifically bind other agents that specifically target IL-1β arepreferred.

Pharmaceutical Compositions and Methods

The anti-IL-1α Ab compositions (and other agents that specificallytarget IL-1α) may be administered to animals or humans inpharmaceutically acceptable carriers (e.g., sterile saline), that areselected on the basis of mode and route of administration and standardpharmaceutical practice. A list of pharmaceutically acceptable carriers,as well as pharmaceutical formulations, can be found in Remington'sPharmaceutical Sciences, a standard text in this field, and in USP/NF.Other substances may be added to the compositions and other steps takento stabilize and/or preserve the compositions, and/or to facilitatetheir administration to a subject.

For example, the Ab compositions might be lyophilized (see Draber etal., J. Immunol. Methods. 181:37, 1995; and PCT/US90/01383); dissolvedin a solution including sodium and chloride ions; dissolved in asolution including one or more stabilizing agents such as albumin,glucose, maltose, sucrose, sorbitol, polyethylene glycol, and glycine;filtered (e.g., using a 0.45 and/or 0.2 micron filter); contacted withbeta-propiolactone; and/or dissolved in a solution including amicrobicide (e.g., a detergent, an organic solvent, and a mixture of adetergent and organic solvent.

The Ab compositions may be administered to animals or humans by anysuitable technique. Typically, such administration will be parenteral(e.g., intravenous, subcutaneous, intramuscular, or intraperitonealintroduction). The compositions may also be administered directly to thetarget site (e.g., the skin) by, for example, topical application. Othermethods of delivery, e.g., liposomal delivery or diffusion from a deviceimpregnated with the composition, are known in the art. The compositionmay be administered in a single bolus, multiple injections, or bycontinuous infusion (e.g., intravenously or by peritoneal dialysis).

A therapeutically effective amount is an amount which is capable ofproducing a medically desirable result in a treated animal or human. Aneffective amount of anti-IL-1a Ab compositions is an amount which showsclinical efficacy in patients as measured by the improvement in one ormore symptoms of skin inflammation. As is well known in the medicalarts, dosage for any one animal or human depends on many factors,including the subject's size, body surface area, age, the particularcomposition to be administered, sex, time and route of administration,general health, and other drugs being administered concurrently.Preferred doses range from about 0.1 to 5 (e.g., 0.05, 0.1, 0.15, 0.2,0.3, 0.4, 0.5, 1, 2, 3, 4, 5, or 6) mg/kg body weight. In some cases asingle dose is effective at resolving an episode of skin inflammation.In other cases, doses may be given repeatedly, e.g., semi-weekly,weekly, bi-weekly, tri-weekly, semi-monthly, once every three weeks,monthly, bi-monthly, or as needed (if skin inflammation recurs).

EXAMPLES Example 1 Xilonix™

Xilonix™ is a sterile injectable liquid formulation of 15 mg/mL MABp1 ina stabilizing isotonic buffer (pH 6.4). Each 10-mL Type I borosilicateglass serum vial contains 5 mL of the formulation, and is sealed with a20-mm Daikyo Flurotec butyl rubber stopper and flip-off aluminum seal.The product is stored at 5±3° C., with excursions to room temperaturepermitted. The exact composition of the drug product is shown below:

Composition of the Drug Product (Xilonix ™) Ingredient GradeManufacturer Concentration MABp1 Ab GMP XBiotech 15 mg/mL sodiumphosphate dibasic compendial J T Baker 12 mg/mL citric acid monohydratecompendial J T Baker 2 mg/mL Trehalose•2H2O (high- compendial Ferro- 60mg/mL purity low endotoxin) Pfanstiehl polysorbate 80 compendial J TBaker 0.2 mg/mL Phosphoric acid, to compendial J T Baker 0.04 mg/mLadjust pH water for injection compendial Microbix q.s.

Method of Administration:

The calculated volume is withdrawn from the drug (mAb)-containingvial(s) using a suitable syringe. The drug is then injected into asubject subcutaneously.

Example 2 Treatment of Acne Vulgaris

An 18-year-old male presented with moderate-to-severe acne vulgarisaffecting his arms, back, chest and face. There was significantinduration of the lesions, particularly on the back. The patientdescribed this as an acute outbreak but reported ongoing acne vulgarisproblems since 15 years of age. Topical retinoids and corticosteroidshad been used in the past with some degree of effectiveness. Alsolimited UV treatment, by use of tanning beds, had been used with limitedresults. The patient was given a single 3 ml subcutaneous injection ofXilonix™ (MABp1; 15mg/ml), representing a dose of 0.6 mg/kg.

The patient was observed for 2 hours post-infusion. There was noapparent infusion reaction, or adverse response to the drug. After24-hours the patient was re-evaluated. Large lesions on the shoulder andback had dramatically reduced in size. Reduced inflammatory infiltrationof facial lesions was evidenced by less redness of the lesions andreduced lesion sizes compared to pre-dose. The lesions appeared to bedrying.

After 72-hours the patient was re-examined. The improvement wasremarkable. Most lesions showed dramatically less inflammation or manywere altogether non-apparent. Lesions on shoulder and back that hadremarkable induration were resolved, only slightly discolored and softto the touch. The patient's face looked essentially normal and thepatient remarked that he was very happy with the appearance of his skin.One week after injection the patient showed continued improvement andall areas of skin appeared without notable lesions.

Example 3 Formulation of MABp1 for Subcutaneous Injection

T2-18C3 is a sterile liquid formulation of 100±5 mg/mL MABp1 in astabilizing isotonic formulation buffer (pH 6.4±0.1). 1.4±0.1 mL of thisformulation was contained within two mL Type I borosilicate glass serumvials sealed with a 20-mm Daikyo Flurotec butyl rubber stopper andflip-off aluminum seal. The product with stored upright at 5±3° C., withexcursions to room temperature permitted. The exact composition of theDrug Product is shown below in Table 2:

TABLE 2 Composition of T2-18C3 Drug Product Ingredient GradeManufacturer Concentration MABp1 antibody GMP XBiotech USA Inc 100mg/mL  trehalose•2H2O GMP, High Ferro- 60 mg/mL purity, Low Pfanstiehl(USA) endotoxin sodium phosphate GMP, EP, J T Baker (USA) 12 mg/mLdibasic USP, JP citric acid GMP, EP, J T Baker (USA)  2 mg/mLmonohydrate USP, BP polysorbate 80 GMP, EP, J T Baker (USA) none NF, JPsterile water GMP, EP, Microbix (Canada) q.s. for injection USP

Example 4 Treatment of Psoriasis

A 48-year old male with a history of Type I psoriasis vulgaris,diagnosed at age 5 was treated with T2-18C3. The patient has a positivefamily history of psoriasis vulgaris, with his sibling, father, andgrandmother being affected as well. He was previously treated withtopical retinoids and vitamin D3 preparations with minimal improvement.Previous treatment with topical steroids and UV treatment showedbenefit. Prior to administration of T2-18C3, the patient had no historyof treatment with biologic agents.

The patient was administered 2 subcutaneous injections of MABp1 in thelower abdomen (a total of 160 mg MABp1) on day 0. The patient toleratedthe injections well, and there were no complications. The patient's backwas evaluated at 17 hours, 41 hours, 5 days, 6 days and 10 dayspost-administration. At 17 hours, a modest improvement in the rednessassociated with the lesions was observed. At 41 hours continuedimprovement was noted with a clearly observable decrease in the size andredness of the lesions. By day 5, significant resolution of the lesionswas observed. This improvement continued through day 6. The lesions werealmost completely resolved by day 10.

Example 5 Treatment of Psoriasis

An open label trial of the True Human™ monoclonal antibody RA-18C3(specific for IL-1alpha) was conducted in human subjects with moderateto severe plaque psoriasis. Trial subjects receive 200 mg of RA-18C3 viasubcutaneous injection at Days 0, 21, and 42 for a total of 3injections. PASI (Psoriasis Area and Severity Index Assessment) scoreswere obtained for each subject at different time points. All of thefirst five evaluable subjects study showed a decrease in PASI score(i.e., improvement of the disease) at day 56. The mean reduction in PASIscores of the first five evaluable subjects at day 56 was almost 50%.

Example 6 Interim Results of A Phase II Open Label Study of the Safety,Pharmacokinetics, and Efficacy of a True Human™ Anti-InflammatoryTherapeutic Antibody (RA-18C3) in Subjects with Moderate to Severe AcneVulgaris

RA-18C3 is a sterile injectable liquid formulation of MABp1 in astabilizing isotonic buffer. The research population consists ofsubjects ≧18 years of age, with moderate to severe acne vulgaris.Subjects had an Investigator's Global Assessment of ≧3, ≧15 inflammatoryfacial lesions, and were candidates for systemic therapy. 11 patientswere enrolled. Seven of the 11 enrolled subjects who had lesion countdata available for day 56 are included in the analysis. Most patients(86%) were Caucasian, median age was 23 (19-30) years, 5 (71%) werefemale. The total facial inflammatory lesion count showed an averageimprovement of 35±8% (median 34%, range 25-48%) on day 42; and 44±23%(median 42%, range 19-71%) on day 56.

The Body Image Disturbance Questionnaire (BIDQ) is a self-administered,clinically validated questionnaire used to assess “negative body image”.The internal consistency, reliability and validity of the 7-item BodyImage Disturbance Questionnaire has been established by several priorstudies, as well as its potential utility in clinical contexts forqualitative analysis. Recently a modified version of the BIDQ wasvalidated specifically for use in patients with acne vulgaris.Self-reported measures of Modified Body Image Disturbance Questionnaire,collected on Day 0 (D0) and Day 21 (D21), were analyzed. This 7-itemsurvey tool assessed different facets of the body image construct,including appearance related concerns, mental preoccupation with thoseconcerns, and resulting impairment of social and occupationalfunctioning. Responding to the first question of BIDQ survey, all 7subjects reported that acne is their primary skin problem and they areconcerned about the appearance of skin. At D21, 43% showed improvementin Mental Preoccupation (Q2), Emotional Distress (Q3), andSocial/occupational impairment (Q4); while 86% showed stabilization withno further worsening in Interference with social life (Q5), Interferencewith school/job (Q6), and Avoidance of activities due to acne problem(Q7). The mean score of the six BIDQ items (Q2 to Q7) showed markedreduction at D21 from the D0 level, which indicates an across the boardimprovement in the body image disturbance.

It has been hypothesized that a causal relationship exists betweenunderlying inflammatory processes present in skin diseases andpsychiatric medical conditions. To further explore this possibility, theHospital Anxiety and Depression Scale (HADS) was used to assess thedepression and anxiety profiles of the trial population. D0 and D21scores were available for all the 7 subjects. The mean anxiety score onD0 and D21 were 6.1±3.1 (median 6.0) and 3.3±3.9 (median 3),respectively (A 2.9) (FIG. 3). As observed from high D0 scores,considerable level of baseline anxiety was prevalent in the studypopulation (median 6). It is important to note that about 50% reduction(from 6.1±3.1 to 3.3±3.9) in anxiety was achieved by D21. The subjectsshowing ≧3 point improvement in anxiety score had a substantial (21% to34%) reduction in “facial inflammatory lesion count” on D21. Meandepression score was 2.6±3.1 (median 1) and 2.1±3.1 (1) on D0 and D21,respectively.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is: 1-6. (canceled)
 7. A method of reducing anxiety in ahuman subject, the method comprising the step of administering to thesubject a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and an amount of an agent that selectively bindsIL-1α effective to reduce anxiety in the subject.
 8. The method of claim7, wherein the agent is an anti-IL-1α antibody.
 9. The method of claim8, wherein the anti-IL-1α antibody is a monoclonal antibody.
 10. Themethod of claim 8, wherein the monoclonal antibody is an IgG1.
 11. Themethod of claim 8, wherein the monoclonal antibody comprises acomplementarity determining region of MABp1.
 12. The method of claim 8,wherein the monoclonal antibody is MABp1.
 13. The method of claim 7,wherein the subject has acne.